Cancer of unknown primary (CUP) is a diagnosis that the primary lesion cannot be confirmed by a series of imaging, endoscopic and pathological examinations. The present study aimed to assess the clinical characteristics and survival outcomes of patients with CUP. The present retrospective observational study included patients diagnosed with malignancies confirmed as CUP using histopathology at the Oncology Department of the Fourth Hospital of Hebei Medical University (Shijiazhuang, China) from January 2009 to January 2021. Clinical and pathological data, genetic testing results, treatment modalities and median overall survival (OS) were analyzed. A total of 107 patients were included, with a mean age of 56.59 years. The median follow-up period was 48.8 months. Adenocarcinoma was the most common pathological type (38.3%), followed by squamous cell carcinoma (31.8%) and neuroendocrine carcinoma (16.8%). The median OS was 28.4 months, with 1-, 2-, 3- and 4-year OS rates of 68.2, 54.1, 48.4 and 42.3%, respectively. Imaging revealed that 31 patients (29%) had visceral metastases, and these patients had a significantly shorter median OS compared with those without visceral metastases (8.9 vs. 69 months; P=0.001). Patients who received local treatment (n=31; 29%) had significantly longer survival times than those who did not (69 vs. 17.9 months; P=0.009). Of the 107 patients, 101 (94.4%) received systemic treatment. The median OS times for different treatment groups were as follows: Chemotherapy alone, 28.4 months; chemotherapy combined with immune checkpoint inhibitors, anti-angiogenic agents or targeted therapy, not reached; no chemotherapy, 8.0 months; and untreated, 9.4 months, with significant differences observed among the groups (P=0.008). The survival outcomes of patients with CUP varied based on the presence of visceral metastasis and the treatment modalities employed. Systemic treatments, particularly those incorporating targeted therapy, appear to have the potential to improve prognosis.